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Controlled human malaria infection (CHMI) using cryopreserved non-attenuated Plasmodium falciparum sporozoites (PfSPZ) offers a unique opportunity to investigate naturally acquired immunity (NAI). By analyzing blood samples from 5 malaria-naïve European and 20 African adults with lifelong exposure to malaria, before, 5, and 11 days after direct venous inoculation (DVI) with Sanaria R PfSPZ Challenge, we assessed the immunological patterns associated with control of microscopic and submicroscopic parasitemia. All (5/5) European individuals developed parasitemia as defined by thick blood smear (TBS), but 40% (8/20) of the African individuals controlled their parasitemia, and therefore remained thick blood smear-negative (TBS - Africans). In the TBS - Africans, we observed higher baseline frequencies of CD4 + T cells producing interferon-gamma (IFNγ) that significantly decreased 5 days after PfSPZ DVI. The TBS - Africans, which represent individuals with either very strong and rapid blood-stage immunity or with immunity to liver stages, were stratified into subjects with sub-microscopic parasitemia (TBS - PCR + ) or those with possibly sterilizing immunity (TBS - PCR - ). Higher frequencies of IFNγ + TNF + CD8 + γδ T cells at baseline, which later decreased within five days after PfSPZ DVI, were associated with those who remained TBS - PCR - . These findings suggest that naturally acquired immunity is characterized by different cell types that show varying strengths of malaria parasite control. While the high frequencies of antigen responsive IFNγ + CD4 + T cells in peripheral blood keep the blood-stage parasites to a sub-microscopic level, it is the IFNγ + TNF + CD8 + γδ T cells that are associated with either immunity to the liver-stage, or rapid elimination of blood-stage parasites., (© 2022. The Author(s).)

Background: Vector control is considered to be the most successful component of malaria prevention programs and a major contributor to the reduction of malaria incidence over the last two decades. However, the success of this strategy is threatened by the development of resistance to insecticides and behavioural adaptations of vectors. The aim of this study was to monitor malaria transmission and the distribution of insecticide resistance genes in Anopheles populations from three rural areas of the Moyen Ogooué Province of Gabon., Methods: Anopheles spp. were collected using human landing catches in Bindo, Nombakélé and Zilé, three villages located in the surroundings of Lambaréné, during both the rainy and dry seasons. Mosquitoes were identified morphologically, and DNA was extracted from heads and thoraces. Members of the Anopheles gambiae complex were identified by molecular methods using the PCR SINE200 protocol and by sequencing of the internal transcribed spacer 2 region. Taqman assays were used to determine Plasmodium infection and the presence of resistance alleles., Results: Anopheles gambiae sensu lato (97.7%), An. moucheti (1.7%) and An. coustani (0.6%) were the three groups of species collected. Anopheles gambiae sensu stricto (98.5%) and An. coluzzii (1.5%) were the only species of the An. gambiae complex present in the collection. Of the 1235 Anopheles collected, 1193 were collected during the rainy season; these exhibited an exophagic behaviour, and consistently more mosquitoes were collected outdoor than indoor in the three study areas. Of the 1166 Anopheles screened, 26 (2.2%) were infected with Plasmodium species, specifically Plasmodium falciparum (66.7%), P. malariae (15.4%), P. ovale curtisi (11.5%) and P. ovale wallikeri (3.8%). Malaria transmission intensity was high in Zilé, with an average annual entomological inoculation rate (aEIR) of 243 infective bites per year, while aEIRs in Bindo and Nombakélé were 80.2 and 17 infective bites per year, respectively. Both the L1014F and L1014S mutations were present at frequencies > 95% but no Ace1G119S mutation was found., Conclusion: Our results demonstrate that malaria transmission intensity is heterogeneous in these three rural areas of Moyen Ogooué Province, with areas of high transmission, such as Zilé. The exophagic behaviour of the mosquitoes as well as the high frequency of resistance mutations are serious challenges that need to be addressed by the deployment of control measures adapted to the local setting., (© 2022. The Author(s).)

Malaria remains one of the deadliest diseases in Africa, particularly for children. While successful in reducing morbidity and mortality, antimalarial treatments are also a major cause of adverse drug reactions (ADRs). Host genetic variation in genes involved in drug disposition or toxicity constitutes an important determinant of ADR risk and can prime for parasite drug resistance. Importantly, however, the genetic diversity in Africa is substantial, and thus, genetic profiles in one population cannot be reliably extrapolated to other ethnogeographic groups. Gabon is considered a high-transmission country, with more than 460,000 malaria cases per year. Yet the pharmacogenetic landscape of the Gabonese population or its neighboring countries has not been analyzed. Using targeted sequencing, here, we profiled 21 pharmacogenes with importance for antimalarial treatment in 48 Gabonese pediatric patients with severe Plasmodium falciparum malaria. Overall, we identified 347 genetic variants, of which 18 were novel, and each individual was found to carry 87.3 ± 9.2 (standard deviation [SD]) variants across all analyzed genes. Importantly, 16.7% of these variants were population specific, highlighting the need for high-resolution pharmacogenomic profiling. Between one in three and one in six individuals harbored reduced-activity alleles of CYP2A6 , CYP2B6 , CYP2D6 , and CYP2C8 with important implications for artemisinin, chloroquine, and amodiaquine therapy. Furthermore, one in three patients harbored at least one G6PD -deficient allele, suggesting a considerably increased risk of hemolytic anemia upon exposure to aminoquinolines. Combined, our results reveal the unique genetic landscape of the Gabonese population and pinpoint the genetic basis for interindividual differences in antimalarial drug responses and toxicity.

Background: Helminths can modulate the host immune response to Plasmodium falciparum and can therefore affect the risk of clinical malaria. We assessed here the effect of helminth infections on both the immunogenicity and efficacy of the GMZ2 malaria vaccine candidate, a recombinant protein consisting of conserved domains of GLURP and MSP3, two asexual blood-stage antigens of P. falciparum. Controlled human malaria infection (CHMI) was used to assess the efficacy of the vaccine., Methodology: In a randomized, double-blind Phase I clinical trial, fifty, healthy, lifelong malaria-exposed adult volunteers received three doses of GMZ2 adjuvanted with either Cationic Adjuvant Formulation (CAF) 01 or Alhydrogel, or a control vaccine (Rabies) on days (D) 0, D28 and D56, followed by direct venous inoculation (DVI) of 3,200 P. falciparum sporozoites (PfSPZ Challenge) approximately 13 weeks after last vaccination to assess vaccine efficacy. Participants were followed-up on a daily basis with clinical examinations and thick blood smears to monitor P. falciparum parasitemia for 35 days. Malaria was defined as the presence of P. falciparum parasites in the blood associated with at least one symptom that can be associated to malaria over 35 days following DVI of PfSPZ Challenge. Soil-transmitted helminth (STH) infection was assessed by microscopy and by polymerase chain reaction (PCR) on stool, and Schistosoma infection was assessed by microscopy on urine. Participants were considered as infected if positive for any helminth either by PCR and/or microscopy at D0 and/or at D84 (Helm+) and were classified as mono-infection or co-infection. Total vaccine-specific IgG concentrations assessed on D84 were analysed as immunogenicity outcome., Main Findings: The helminth in mono-infection, particularly Schistosoma haematobium and STH were significantly associated with earlier malaria episodes following CHMI, while no association was found in case of coinfection. In further analyses, the anti-GMZ2 IgG concentration on D84 was significantly higher in the S. haematobium-infected and significantly lower in the Strongyloides stercoralis-infected groups, compared to helminth-negative volunteers. Interesting, in the absence of helminth infection, a high anti-GMZ2 IgG concentration on D84 was significantly associated with protection against malaria., Conclusions: Our results suggest that helminth infection may reduce naturally acquired and vaccine-induced protection against malaria. Vaccine-specific antibody concentrations on D84 may be associated with protection in participants with no helminth infection. These results suggest that helminth infection affect malaria vaccine immunogenicity and efficacy in helminth endemic countries., Competing Interests: The authors have declared that no competing interests exist.